Dynamic diastereoselectivity during iron carbonyl mediated spirocyclization reactions

Article abstract of DOI:10.1021/jo0625608

Dynamic diastereoselectivity during Fe(CO)₃ promoted [6 + 2] ene spirocyclization of 35a and 35b, having a chiral center on the pendent side chain, was investigated and gave rise to products 28a and 28b instead of four possible isomers. From th

Full text of DOI:10.1021/jo0625608

Dynamic Diastereoselectivity during Iron Carbonyl Mediated
Spirocyclization Reactions
Anthony J. Pearson,* Huikai Sun, and Xiaolong Wang
Department of Chemistry, Case Western ReserVe UniVersity, CleVeland, Ohio 44106
ajp4@case.edu
ReceiVed December 13, 2006
Dynamic diastereoselectivity during Fe(CO)3 promoted [6 + 2] ene spirocyclization of 35a and 35b,
having a chiral center on the pendent side chain, was investigated and gave rise to products 28a and 28b
instead of four possible isomers. From this reaction, two chiral centers are generated, with absolute
stereochemistry determined by the double bond geometry and the chiral center already present. 28a/b
and the diene product from demetallation of 28a are proposed as potential intermediates for total synthesis
of 18-deoxycytochalasin H. Furthermore, a stepwise second cyclization and a tandem double cyclization
mediated by the Fe(CO)3 moiety was investigated.
SCHEME 1. An Example of Fe(CO)3 Promoted [6+2] ene
Type of Spirocyclization
Introduction
The iron(0) tricarbonyl moiety has been widely applied to
promote isomerization of olefinic compounds,1 formation of
carbon-carbon bonds, and for diene protection2 because of its
compatibility with a wide range of functional groups, environ-
mentally friendly nature, and efficient catalytic ability. The Fe-
(CO)3 moiety can also be used as a stereochemical directing
group during reactions of neighboring functionality.3
A few years ago, an Fe(CO)3 promoted [6 + 2] ene type of
cyclization was developed in our laboratory to provide spiro-
cyclic lactams as final products.4 A simple example is outlined
in Scheme 1, although the pendent double bond in the substrate
can be further substituted with a variety of functional groups.
Initially, subjection of substrates 1a and 1b, a pair of intercon-
vertible enantiomers derived from racemic complexed acids, to
thermal reaction conditions affords lactams 2a and 2b, respec-
tively. While the actual cyclization is stereospecific, subsequent
rearrangement of the diene in lactam 2a, via an iron-mediated
hydride shift, produces compound 3a and, similarly, 3b is
obtained from 2b. Finally, four isomers, two pairs of enanti-
omers (2a/3a and 2b/3b), are provided through this spirocy-
clization reaction. While several approaches4,5 have been
developed to control the loss of regio- or stereochemistry caused
by postcyclization diene rearrangement, none of them adequately
address the racemization caused by precyclization interconver-
sion of two substrate enantiomers. To a great extent, the
application of this methodology to organic synthesis is limited
by all the above disadvantages. Our previous work also showed
precyclization racemization could be avoided by introduction
(1) Uma, R.; Crevisy, C.; Gre´e, R. Chem. ReV. 2003, 103, 27-51.
(2) (a) Pearson, A. J. Iron Compounds in Organic Synthesis; Academic
Press: San Diego, CA, 1994. (b) Evans, G.; Johnson, B. F. G.; Lewis, J. J.
Organomet. Chem. 1975, 102, 507.
(3) (a) Gre´e, R. Synthesis 1989, 341. (b) Pearson, A. J.; Srinivasan, K.
J. Org. Chem. 1992, 57, 3965-3973. (c) Pearson, A. J.; Yoon, J.
Tetrahedron Lett. 1985, 26, 2399-2402.
(4) Pearson, A. J.; Zettler, M. W. J. Am. Chem. Soc. 1989, 111, 3908-
3918.
(5) (a) Pearson, A. J.; Wang, X. J. Am. Chem. Soc. 2003, 125, 638-
639. (b) Pearson, A. J.; Dorange, I. B. J. Org. Chem. 2001, 66, 3140-
3145.
10.1021/jo0625608 CCC: $37.00 © 2007 American Chemical Society
Published on Web 03/01/2007
J. Org. Chem. 2007, 72, 2547-2557
2547

Pearson et al.
SCHEME 2. Synthesis of Substrates 9a and 9ba
a Reagents and conditions: (a) Triethyl phosphonoacetate, BuLi, THF, -78 °C, then 5 in THF -78-0 °C, 53%. (b) TFA, CH2Cl2, 0 °C, 96%. (c) 8,
DIEA, MsCl, CH2Cl2, 0 °C, then 7, rt, 82%.
SCHEME 3. Spirocyclization of Substrates 9a and 9ba
a /lp;&-5q;1Reagents and conditions: (a) n-Bu2O, CO, 142 °C. (b) Sat. CuCl2 in EtOH. (c) 10% Pd/C, H2, MeOH, 50% yield over three steps.
of substituents on the cyclohexadienyl ring, but this requires
an often difficult optical resolution of the starting material.6 This
inspired us to further explore the stereochemistry of this
cyclization reaction to obtain optically pure products. Our
investigation focused on what is essentially a dynamic kinetic
resolution using substrates with a chiral center on the pendent
side chain. We also consider its potential application to the total
synthesis of 18-deoxycytochalasin H, a natural product that is
a potent HIV-1 protease inhibitor. A preliminary communication
of part of this work has previously been published.7
(4).8 Unsaturated ester E-6 was obtained from aldehyde 5
through a Horner-Wadsworth-Emmons reaction,9 accompa-
nied by formation of the Z isomer (E:Z/1.4:1), which was
separated chromatographically. Amine deprotection occurred by
treatment with TFA to afford 7 quantitatively, which was
coupled with racemic complexed acid 8 to afford the expected
substrates, two diastereomers 9a and 9b, in 82% combined yield.
Heating substrates 9a and 9b in n-Bu2O under CO atmosphere
at 142 °C generated several inseparable products which could
1
not be fully characterized by H NMR spectroscopy. Without
further purification, the mixture of these products was demet-
allated with CuCl2, followed by hydrogenation over 10% Pd/C
to lead to two major products, 12a and 12b in ratio of 1.5 to 1,
in 50% isolated yield over three steps. Compounds 12a and
12b were easily characterized and the stereochemistry of 12a
was determined from the NOE difference NMR spectrum.
On the basis of our understanding of the likely mechanism,
the spirocyclization of substrates 9a and 9b is outlined in
Scheme 3 and involves reaction intermediates 10a and 10b. The
Results and Discussion
Considering the ready accessibility of starting material and
the possibility that introduction of a chiral center on the pendent
olefinic side chain can produce, to some extent, a new chirality
inducing factor, substrates 9a and 9b were designed and
prepared starting with the known aldehyde 5 (Scheme 2), which
was derived in 59% yield over four steps from L-phenylalanine
(6) (a) Pearson, A. J.; Zettler, M. W. J. Chem. Soc., Chem. Commun.
1987, 1243-1245. (b) Birch, A. J.; Bandara, B. M. R. Tetrahedron Lett.
1980, 21, 2981-2982.
(8) Dondoni, A.; Perrone, D.; Merino, P. J. Org. Chem. 1995, 60, 8074-
8080.
(9) Udwary, D. W.; Casillas, L. K.; Townsend, C. A. J. Am. Chem. Soc.
2002, 124, 5294-5303.
(7) Pearson, A. J.; Wang, X. Tetrahedron Lett. 2005, 46, 3123-3126.
2548 J. Org. Chem., Vol. 72, No. 7, 2007

Dynamic DiastereoselectiVity during Spirocyclization
SCHEME 4. Preparation of Substrates 18a and 18ba
SCHEME 5. Preparation of 17a and 17b from Racemic
Amine 16a
a Reagents and conditions: (a) DBU, LiCl, MeCN, 0 °C, 85%. (b) Ethyl
2-(diethoxyphosphoryl)propionate, DBU, LiCl, MeCN, 0 °C, 69%. (c) TFA,
CH2Cl2, quantitatively. (d) Mosher’s chloride, DIEA, CH2Cl2, racemic amine
16, 41% for 17a and 42% for 17b.
Cl2)11 gave even poorer ee, 71%, for compound 16. So, finally,
secondary amine 16 prepared using method A was taken on to
the coupling reaction with racemic complexed acid 8 to provide
the desired substrates 18a and 18b. Deprotection of compound
14 spontaneously afforded lactam 15 instead of the correspond-
ing free secondary amine, which is also the reason why only
substrates 18a and 18b with pendent E olefin were prepared
via this route. The analogous Z olefins were obtained by a
different route, described later.
a Reagents and conditions: (a) Method A: ethyl 2-(diethoxyphospho-
ryl)propionate, BuLi, THF, -78 °C, 67% for 13, 14% for 14; method B:
ethyl 2-(diethoxyphosphoryl)propionate, DBU, LiCl, MeCN, 0 °C, 65%
for 13, 13% for 14; method C: (carbethoxyethylidene)triphenylphosphorane,
CH2Cl2, 73% for 13, 13% for 14. (b) TFA, CH2Cl2, quantitatively. (c)
Mosher’s chloride, DIEA, CH2Cl2, amine 16, method A: 82%, ee ) 94%;
method B: 78%, ee ) 74%; method C: 85%, ee ) 71%. (d) 8, DIEA,
MsCl, CH2Cl2, 0 °C, then 16, rt, 81%.
As mentioned above, the optical purity of free amine 16 was
determined by conversion to Mosher amides 17a and 17b. The
1H NMR spectrum of 17a/b showed four isomers in different
ratios, which made optical purity measurement difficult because
of the uncertainty concerning the presence of amide resonance
rotamers of 17a and 17b. To confirm this, racemic amine 16
was prepared (Scheme 5). First, aldehyde 5 was racemized by
treatment with DBU in the presence of LiCl in acetonitrile,
confirmed by the change of specific rotation from -131 to 0.
Subsequent subjection of racemic 5 to method B conditions
described in Scheme 4, followed by Boc-removal with TFA
and amidation with Mosher’s chloride, provided two chromato-
graphically separable products 17a and 17b in 1:1 ratio. Variable
temperature 1H NMR spectra confirmed the presence of rotamers
facial orientation of the prochiral alkene side chain shown for
10a/b corresponds to that which leads to the stereochemistry
shown for the conversion of 1a to 2a/b in Scheme 1. Since
both demetallation and hydrogenation were complete, the ratio
of direct cyclization products 11a/a′ over 11b/b′ can also be
deduced as 1.5 to 1 from the ratio of 12a over 12b. Considering
the difference in configurations of intermediates 10a and 10b,
we speculate that the stereoselectivity of this reaction is due to
different steric hindrance effects in these structures. In inter-
mediate 10b, eclipsed Ha and Bn experience a repulsive
interaction, which is relieved in 10a because Ha and Hb are now
eclipsed. Therefore, the spirocyclization reaction favors the
pathway through intermediate 10a, and equilibration between
9a and 9b (via metal-mediated H-shifts) gives rise to 11a as
the major product. Even though the stereoselectivity was not
as good as we hoped, these results encouraged us to investigate
this reaction further.
Replacement of Ha with a sterically more demanding sub-
stituent should introduce greater steric hindrance in intermediate
10b, which may lead to much better stereocontrol if our rationale
on the selectivity is correct. On the basis of this proposition,
substrates 18a and 18b were prepared (Scheme 4) starting with
aldehyde 5 via a Horner-Wadsworth-Emmons reaction.
Several reaction conditions were applied for conversion of
aldehyde 5 to compounds 13 and 14. Method A (ethyl
2-(diethoxyphosphoryl) propionate, n-BuLi, THF, -78 °C)
furnished 67% of 13 and 14% of 14, and further Boc depro-
tection of compound 13 gave rise to free secondary amine 16
with 94% ee, which was determined by converting amine 16 to
Mosher amides 17a and 17b. Method B (ethyl 2-(diethoxy-
phosphoryl) propionate, LiCl, DBU, MeCN, 0 °C)10 afforded
65% and 13% of 13 and 14, respectively, however, the
deprotection product 16 showed only 74% ee. The milder
method C ((carbethoxyethylidene) triphenylphosphorane, CH2-
1
for both of them. Comparison with these H NMR spectra
allowed determination of the optical purity of amines 16
prepared earlier.
With substrates 18a and 18b in hand, spirocyclization was
investigated under thermal conditions (in n-Bu2O, reflux, and
under CO atmosphere). Gratifyingly, only spirocyclic lactams
20a and 20a′ were isolated and no compounds 20b or 20b′ could
be observed in the crude mixture of products (Scheme 6). These
results indicate that the increased steric hindrance between
methyl and benzyl groups in 19b suppresses formation of this
intermediate, and spirocyclization proceeds only via intermediate
19a. Equilibration between 18a and 18b under these reaction
conditions channels the conversion through 19a to afford only
20a which subsequently rearranges to afford the mixture of 20a
and 20a′. These results further support our rationale on the
diastereoselectivity of this type of spirocyclization. However,
only 35% of expected products 20a and 20a′ were obtained
reproducibly under thermal conditions. Major side products were
characterized to be 22a and 22b in 9:1 ratio and in 36% yield,
which might be derived from demetallated intermediate 21
followed by an immediate intramolecular Diels-Alder reaction.
Compounds 22a and 22b were confirmed to be products of
(11) (a) Horigome, M.; Motoyoshi, H.; Watanabe, H.; Kitahara, T.
Tetrahedron Lett. 2001, 42, 8207-8210. (b) Nieman, J. A.; Coleman, J.
E.; Wallace, D. J.; Piers, E.; Lim, L. Y.; Roberge, M.; Andersen, R. J. J.
Nat. Prod. 2003, 66, 183-199.
(10) Dixon, D. J.; Foster, A. C.; Ley, S. V. Org. Lett. 2000, 2, 123-
125.
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Pearson et al.
SCHEME 6. Spirocyclization of Substrates 18a and 18ba
a Reagents and conditions: (a) Benzene, CO, 85 °C, 350 nm, 67% for compound 20a and 20a′, 4% for decomplexed 20a and 20a′, 12% for 22a and 22b.
(b) 10% Pd/C, H2, MeOH, 98%. (c) Method A: Me3NO, benzene, 81%; Method B: sat. CuCl2 in EtOH, 83%. (d) 10% Pd/C, H2, MeOH, 88%. (e) LiBH4,
Et2O, 90%. (f) Mosher’s chloride, DIEA, toluene, 100 °C, 72%.
SCHEME 7. Investigation of Diels-Alder Reaction on the
Basis of Substrate 18a and 18b
endo/exo cycloaddition by converting them to a single hydro-
genation product, 23. After a series of optimization experiments,
photothermal reaction conditions (benzene, CO, 85 °C, 350 nm)
afforded the best yield, 67%, for compounds 20a and 20a′ with
formation of their demetallation products in 4% yield, and
Diels-Alder products 22a and 22b in 12% yield. Then,
demetallation with copper(II) chloride in ethanol followed by
hydrogenation converted products 20a and 20a′ to the same
compound 24, whose optical purity was determined (ee > 94%)
through reduction with LiBH4, followed by esterification with
Mosher’s chloride to furnish compound 25. Thus, no stereo-
chemical leakage occurs throughout the reaction sequence, and
the cyclization event itself is stereospecific.
As previously mentioned, major side products during the
reaction in Scheme 6 were two [4 + 2] cycloaddition products
in 9:1 ratio. Treatment of 18a and 18b with copper(II) chloride
at room temperature also gave compounds 22a and 22b in 9:1
ratio and in 86% yield (Scheme 7). However, we did not have
synthesis of compound 21 via the acyl mesylate from acid 2612
and amine 16 afforded only 22a and 22b in 9:1 ratio and in
84% yield. This result confirms that uncomplexed compound
21 undergoes spontaneous intramolecular Diels-Alder reaction
any proof whether this cyclization might be promoted by the
Fe(CO)3 moiety or derived directly from demetallated compound
(12) Grade´n, H.; Hallberg, J.; Kann, N.; Olsson, T. J. Comb. Chem. 2004,
21, via a simple intramolecular Diels-Alder reaction. Attempted
6, 783-788.
2550 J. Org. Chem., Vol. 72, No. 7, 2007

Dynamic DiastereoselectiVity during Spirocyclization
SCHEME 8. A Possible Approach to 18-Deoxycytochalasin
H
SCHEME 9. Preparation and Spirocyclization Reaction of
Substrates 35a and 35ba
as soon as it is formed. More importantly, it further confirms
the need to use diene-Fe(CO)3 complexes stoichiometrically,
because coordination of the diene with Fe(CO)3 prevents Diels-
Alder cycloaddition and allows the substrate to follow a [6 +
2] ene pathway, thereby increasing molecular diversity that is
accessible from such materials.
18-Deoxycytochalasin H (Scheme 8) is a potent HIV-1
protease inhibitor, and its derivatives can regulate plant growth.13
The presence of a densely substituted spirolactam skeleton in
its structure attracted our interest because this type of subunit
is produced from our ene type cyclization. One can envision
18-deoxycytochalasin H to be accessible from an intermediate
such as 27 by further manipulation of the cyclohexadiene, and
27 might in turn be available from 28a/b. Alternatively, 27 might
also be available from 29a, which can be obtained from
demetallation of 28a, via a series of transformations. As
intermediates for total synthesis, compounds 29a and 28a/b
require S, S, and S chirality at C3, C4, and C11, respectively,
however, compounds 20a and 20a′, prepared from the spiro-
cyclization reaction in Scheme 6, show one different chiral
center, R, at C11. On the basis of our understanding of the
mechanism of this [6 + 2] ene spirocyclization reaction,
intermediate 29a with the same chirality as 18-deoxycytocha-
lasin H, or its complexed precursors, 28a and 28b, should be
accessible from precursors 35 (Scheme 9) having a pendent
trisubstituted Z olefin.
a Reagents and conditions: (a) NaOH, MeOH, then p-methoxybenzal-
dehyde, AcOH, MeOH, 0 °C; NaBH4, 82%. (b) Mosher’s chloride, DIEA,
reflux, 91%. (c) 8, DIEA, MsCl, CH2Cl2, 0 °C, then 31, 40 °C, 75%. (d)
DIBAl-H, Et2O, -78 °C, 80%. (e) Ethyl 2-[bis(2,2,2-trifluoroethyl)phospho-
no]propionate, KH, THF, -78 °C, 70%. (f) Benzene, CO, 350 nm, 85 °C,
72%. (g) Sat. CuCl2 in EtOH, 80%. (h) 10% Pd/C, H2, MeOH, 84% (ee >
86%). (i) LiBH4, Et2O. (j) Mosher’s chloride, DIEA, benzene, 80 °C, 70%
over two steps.
SCHEME 10. Diels-Alder Reaction from Substrates 35a
and 35ba
Since deprotection of compound 14 resulted in spontaneous
cyclization to give lactam 15 instead of a free secondary amine
(Scheme 4), substrates 35a and 35b were prepared as outlined
in Scheme 9 starting with ethyl L-phenylalanine hydrochloride
(30). Known secondary amine 3114 was prepared according to
a published procedure15 by treating 30 with sodium hydroxide
followed by anisaldehyde and a catalytic amount of acetic acid
and then reduction with lithium borohydride. The optical purity
of secondary amine 31 (ee ) 100%) was also determined by
conversion to the Mosher amide 32. As far as we are aware,
the optical purity of 31 obtained by this route has not previously
been determined. Subsequent coupling of amine 31 with
complexed acid 8 led to amide 33, as two diastereomers, which
could be converted in 56% yield over two steps to substrates
a Reagents and conditions: (a) Benzene, CO, 350 nm, 85 °C, 14%, side
product from spirocyclization. (b) Sat. CuCl2 in EtOH, 81%.
35a and 35b through DIBAl-H reduction and a Still-Gennari
phosphonate olefination reaction.16
As expected, subjection of substrates 35a and 35b to
photothermal conditions furnished spirocyclic lactams 28a and
28b, two diastereomers, as the only [6 + 2] ene spirocyclization
products in 72% yield. As before, excellent dynamic diastereo-
selectivity resulted from different steric hindrance in the two
diastereomeric reaction intermediates. We also isolated 4%
(13) Haidle, A. M.; Myers, A. G. Proc. Natl. Acad. Sci. 2004, 101,
12048-12053.
(14) Bonache, M. A.; Cativiela, C.; Garcia-Lopez, M. T.; Gonzalez-
Muniz, R. Tetrahedron Lett. 2006, 47, 5883-5887.
(15) Verardo, G.; Geatti, P.; Pol, E.; Giumanini, A. G. Can. J. Chem.
2002, 80, 779-788.
(16) (a) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405-
4408. (b) Dakin, L. A.; Langille, N. F.; Panek, J. S. J. Org. Chem. 2002,
67, 6812-6815.
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Pearson et al.
SCHEME 11. Exploration of a Second Fe(CO)3 Promoted Cyclizationa
a Reagents and conditions: (a) DIBAl-H, Et2O, -78 °C, 77%. (b) Methyltriphenylphosphonium bromide, n-BuLi, THF, 0 °C to rt, 92%. (c) Mesitylene,
CO, 350 nm, 160 °C, 52%. (d) Sat. CuCl2 in EtOH, 72%.
combined yield of compounds 20a and 20a′, which we attribute
to formation of substrates 18a and 18b through Z double bond
isomerization of 35a and 35b under the reaction conditions.
Diels-Alder reaction products were also formed through
decomplexed intermediate 38 to give rise to compound 39, in
this case in 14% yield (Scheme 10). When substrates 35a and
35b were subjected to demetallation (sat. CuCl2 in EtOH), the
product 38 underwent spontaneous Diels-Alder reaction to
provide 39 as a single stereoisomer in 81% yield. This also
confirmed that the [6 + 2] ene spirocyclization reaction,
described in Scheme 9, needs to be promoted by stoichiometric
Fe(CO)3 and is not directly accessible from 38 by any catalytic
FIGURE 1. Determination of the stereochemistry for compound 43.
method.
undergoes cyclization to afford 42. Treatment of 42 with copper
chloride in ethanol furnished demetallated compound 43 in 72%
yield.
Compounds 28a and 28b were demetallated with copper
chloride in ethanol to afford decomplexed dienes 29a and 29b
in 80% yield, which were hydrogenated to a single compound
36 in 84% yield. We attempted to determine the optical purity
of compound 36 by conversion to the Mosher ester 37, 1H NMR
of which indicated its diastereomeric purity to be greater than
86%, but this could not be determined accurately. On the basis
of analysis of the reactions in Scheme 9, the most likely point
for partial racemization to occur is during conversion of
aldehyde 34 to substrates 35a and 35b in the presence of a strong
base, KH, and not during the spirocyclization reaction.
The stereochemistry of compound 43 was confirmed by 2D
COSY and NOESY spectra (Figure 1). A strong NOE was
observed between Me5a protons and H3 and H4 and both of H3a
and H3b, but no NOE was observed between H3 and H5, which
indicated that the stereochemical relationship is trans for H3
with H4 and cis for H4 with H5. Since the chirality of C7 is
fixed by the reaction mechanism via alkene coordination to Fe,
the stereochemistry at C6 was confirmed by the cis relationship
between H6 and H7, which results in a strong NOE between
them, and no NOE between H7 and Me6a, while the latter
showed strong NOE with H8. This assignment also confirms
the S stereochemistry assigned for the side chain propionate
moiety of 29a/b discussed earlier. While 43 is clearly not
convertible to 27, and therefore is not a viable intermediate on
route to 18-deoxycytochalasin H, the success of this tandem
sequence provides the impetus for development of a more
appropriate homologous reaction.
The success of the above stepwise second Fe(CO)3 promoted
cyclization encouraged us to explore a tandem double cyclization
on the basis of a substrate with a conjugated diene in the pendent
side chain. The involvement of the iron complex in multiple
steps described in Schemes 9 and 11 might be avoided through
this tandem approach. Substrate 48 was prepared starting with
intermediate 14, which was the side product during preparation
of 13. Reduction of 14 with DIBAl-H at rt led to alcohol 44 in
92% yield. Subsequent attempts to oxidize allylic alcohol 44
to Z-R, â unsaturated aldehyde 45 with MnO2, PCC, Dess Martin
reagent, or Swern oxidation were compromised because double
bond isomerization occurred to give rise to E-R, â unsaturated
The stereochemistry at C3 and C4 in compounds 29a and
29b was confirmed by NOESY, however, the chirality of C11
on the side chain of this spirocyclic structure was assigned to
be S on the basis of the reaction mechanism but could not be
confirmed by NMR spectroscopy. Meanwhile, we also wanted
to explore the possibility of a second cyclization reaction through
introduction of a second double bond on the side chain.
Substrates for this model study, 41a and 41b, were prepared
from spirocyclization products 28a and 28b through a reduction
of ester to aldehydes 40a and 40b and subsequent Wittig
reaction (Scheme 11). Investigation of the [6 + 2] ene-type
cyclization of 41a/b showed that the best isolated yield, 52%
with 25% of recovered starting materials, was obtained using
more forcing photothermal conditions in mesitylene at 160 °C
for 9 h, affording 42 as the only characterizable product.
Prolonged reaction time gave poorer yield, possibly because of
decomposition of product 42 at high temperature. On the basis
of the reaction mechanism, only substrate 41a can directly
undergo cyclization to afford compound 42; however, substrate
41b is isomerized to 41a under thermal equilibration and then
2552 J. Org. Chem., Vol. 72, No. 7, 2007

Dynamic DiastereoselectiVity during Spirocyclization
SCHEME 12. Investigation of a Tandem Double
Cyclization Mediated by the Fe(CO)3 Moietya
Experimental Section
General Procedure for the Thermally Induced Cyclization.
The appropriate amide was dissolved in freshly distilled n-Bu2O
ether (0.02 mmol/mL) under argon in a dried glass round bottomed
flask. The air in the solution was removed by freeze-pump-thaw
method three times, followed by bubbling with Ar for 10 min and
then with CO for 10 min. The solution was refluxed under a balloon
of CO for 8-20 h. The cooled reaction mixture was filtered through
Celite and was concentrated in vacuo. Flash chromatography or
preparative TLC separation yielded the desired products. Deviations
from this procedure are noted in the experimental description for
specific compounds.
General Procedure for the Photothermally Induced Cycliza-
tion. The appropriate amide was dissolved in freshly distilled
toluene, xylene, or mesitylene (0.01-0.02 mmol/mL) under argon
in a dried quartz tube or a glass round bottomed flask. The air in
the solution was removed by freeze-pump-thaw method three
times followed by bubbling with Ar for 10 min and then with CO
for 10 min. The reaction flask was put into an oil bath heated to
the boiling point of the solvent being used and was irradiated in a
Rayonet reactor with a 350-nm light source with magnetic stirring
for 3-24 h under a balloon of CO. The cooled reaction mixture
was filtered through Celite and was concentrated in vacuo. Flash
chromatography or preparative TLC separation yielded the desired
products. Deviations from this procedure are noted in the experi-
mental description for specific compounds.
General Procedure for Demetallation. Method A: To the
solution of complexed intermediate in benzene was added trim-
ethylamine oxide (30 equiv). The reaction mixture was stirred for
24 h at rt and then was filtered through Celite and was concentrated
in vacuo. Purification by flash chromatography or preparative TLC
afforded the pure products. Method B: To a small vial was added
the iron carbonyl complex (0.1 mmol) and sat. CuCl2 solution in
EtOH (2.5 mL). The solution was stirred at rt for 18-24 h and
then was concentrated in vacuo. After water (4 mL) was added to
the residue, the mixture was extracted with ether (3 mL × 3). The
organic layer was washed with brine, was dried (Na2SO4), was
filtered, and was concentrated in vacuo. The crude products were
purified by preparative TLC or flash chromatography.
[(4S,2E)-Ethyl 4-(N-(4-methoxybenzyl)cyclohexa-1,3-diene-
carboxamido)-5-phenylpent-2-enoate]tricarbonyliron (9a and
9b). To a solution of complexed carboxylic acid 8 (123 mg, 0.47
mmol) and diisopropylethylamine (92 µL, 0.56 mmol) in freshly
distilled CH2Cl2 (6.0 mL) under argon at 0 °C was quickly added
methanesulfonyl chloride (47 µL, 0.60 mmol). Stirring was
continued at this temperature for 1 h. Diisopropylethylamine (169
µL, 1.02 mmol) was added followed by a solution of amine 7 (236
mg, 0.70 mmol) in freshly distilled CH2Cl2 (2.0 mL). The
temperature was allowed to reach rt and then the reaction mixture
was stirred for 24 h. After CH2Cl2 (15 mL) was added, the organic
layer was washed with 1 N HCl (5 mL × 2) and brine (5 mL × 2),
was dried (Na2SO4), was filtered, and was concentrated in vacuo.
Flash chromatography (Hex:EA/4:1) allowed partial separation of
9a and 9b (223 mg, 82% combined yield). One diastereomer: Rf
) 0.50 (Hex:EA/4:1). [R]D25 ) -29 (c ) 0.84, CHCl3). 1H NMR
(400 MHz, CDCl3): δ7.25-7.05 (7H), 6.92 (br, 1H), 6.81 (dt, J
) 8.8, 2.0 Hz, 2H), 6.16 (br, 1H), 5.56 (br, 1H), 5.28 (br, 1H),
4.42 (br, 1H), 4.13 (q, J ) 7.2 Hz, 2H), 3.80 (s, 3H), 3.83-3.70
(m, 1H), 3.52-3.40 (2H), 3.05 (br, 1H), 1.92-1.62 (3H), 1.42-
1.36 (m, 1H), 1.23 (t, J ) 6.8 Hz, 3H). 13C NMR (100 MHz,
CDCl3): δ 174.2, 166.2, 159.3, 146.0, 129.7, 128.9, 128.7, 126.9,
122.7, 114.4, 85.7, 70.8, 64.6, 62.1, 60.6, 55.5, 53.6, 38.0, 27.0,
23.9, 14.4. HRMS (FAB) calcd for MH+ (C31H32FeNO7) 586.1528,
found, 586.1529. The other diastereomer: Rf ) 0.51 (Hex:EA/4:
1). [R]D25 ) -53 (c ) 0.90, CHCl3). 1H NMR (400 MHz, CDCl3):
δ7.27-7.05 (8H), 6.88 (d, J ) 8.4 Hz, 2H), 5.97 (d, J ) 4.0 Hz,
1H), 5.56 (d, J ) 16.4 Hz, 1H), 5.23 (dd, J ) 6.0, 4.8 Hz, 1H),
4.84 (d, J ) 15.6 Hz, 1H), 4.13 (q, J ) 68 Hz, 2H), 4.22-4.05
a Reagents and conditions: (a) DIBAl-H, CH2Cl2, rt, 92%. (b)
Fe(CO)4PPh3, Me3NO, benzene, 71%. (c) Methyltriphenylphosphonium
bromide, n-BuLi, THF, -78 °C - rt, 85%. (d) Me3SiI, CHCl3, 50 °C, then
acetic acid, 53%. (e) 8, DIEA, MsCl, CH2Cl2, 0 °C, then 47, 40 °C, 83%.
(f) Benzene, CO, 350 nm, reflux, 10%.
aldehyde which was inseparable from 45. Recently, a new
method for oxidation of allylic alcohols to aldehydes was
developed in our laboratory by using Fe(CO)4PPh3 as catalyst
and Me3NO as oxidant in benzene solution.17 Subjection of 44
to this reaction afforded aldehyde 45 in 71% yield without any
formation of E isomer. Diene 46 was obtained through a Wittig
reaction in the presence of methyltriphenylphosphonium bro-
mide and n-BuLi, and subsequent Boc removal with Me3SiI
gave rise to free secondary amine 47 in 53% yield,18 which
was used in the next step without further purification. Finally,
coupling of amine 47 with racemic complexed acid 8 furnished
the desired substrate 48 as two diastereomers. Unfortunately,
subjection of 48 to photothermal conditions in benzene provided
only 10% of expected product 42, accompanied by many
uncharacterized side products. Other attempts under different
reaction conditions led to even poorer yield. Consequently, the
better approach to these multicyclic structures is via the
interrupted tandem sequence of Schemes 9 and 11.
Conclusions
We have shown that spirocyclization using our iron-promoted
[6 + 2] ene-type reaction can be used to produce densely
substituted spirolactams in high optical purity, using a single
stereogenic center as a control element. This procedure is akin
to a dynamic kinetic resolution and allows a racemic mixture
of planar chiral diene iron complexes such as 8 to be converted
to a single enantiomer of the product. A second ene-type
cyclization allows the construction of a tricyclic structure, again
with complete stereocontrol. Provided this second cyclization
can be engineered to produce a six-membered ring as in structure
27 (rather than the five-membered ring from the present work),
we envision that this technology can be used to produce the
main structural features present in the 18-deoxycytochalasin H
molecule. Those studies are currently underway in our labora-
tory.
(17) Pearson, A. J.; Kwak, Y. Tetrahedron Lett. 2005, 46, 5417-5419.
(18) Takeuchi, H.; Fujimoto, T.; Hoshino, K.; Motoyoshiya, J.; Kakehi,
A.; Yamamoto, I. J. Org. Chem. 1998, 63, 7172-7179.
J. Org. Chem, Vol. 72, No. 7, 2007 2553

Pearson et al.
(2H), 3.80 (s, 3H), 3.38-3.36 (m, 1H), 3.20-3.10 (br, 2H), 1.96-
1.80 (2H), 1.78-1.64 (m, 1H), 1.44-1.33 (m, 1H), 1.24 (t, J )
6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 173.9, 166.3, 159.4,
146.3, 138.2, 129.5, 128.9, 128.8, 128.7, 126.9, 122.4, 114.5, 85.1,
84.7, 77.4, 64.1, 61.2, 60.6, 55.5, 38.0, 27.0, 26.5, 24.7, 14.4. HRMS
(FAB) calcd for MH+ (C31H32FeNO7) 586.1528, found, 586.1556.
Ethyl 2-[(3S,4S)-3-benzyl-2-(4-methoxybenzyl)-1-oxo-2-zaspiro-
[4.5]decan-4-yl]acetate (12a) and Ethyl 2-[(3S,4R)-3-benzyl-2-
(4-methoxybenzyl)-1-oxo-2-azaspiro[4.5]decan-4-yl]acetate (12b).
The mixture of 9a and 9b (71 mg, 0.121 mmol) in n-Bu2O (8 mL)
was subjected to thermal cyclization conditions under reflux for
12 h. Rapid purification by flash chromatography (Hex:EA/2:1)
afforded 11a and 11b together with three other isomers, which were
inseparable and were used without further purification. According
to general procedure method A for demetallation, to the above
mixture was added sat. CuCl2 in ethanol (2.0 mL). Stirring was
continued for 18 h. Evaporation in vacuo gave the crude products
as a pale yellow oil. To a solution of this oil in MeOH (4.0 mL)
was added 10% Pd/C (39 mg), and the mixture was stirred under
H2 for 15 h. After filtration to remove the catalyst, the solvent was
evaporated in vacuo. Purification by flash chromatography (hexanes:
EA/2:1) afforded compounds 12a and 12b in 1.5:1 ratio and in
50% combined yield over three steps. 12a: Rf ) 0.50 (Hex:EA/
1H), 1.37 (d, J ) 1.60 Hz, 3H), 1.22 (t, J ) 7.2 Hz, 3H). 13C
NMR (50 MHz, CDCl3): δ 174.2, 167.8, 159.1, 138.5, 138.1, 129.9,
129.5, 128.5, 128.4, 128.3, 126.5, 114.2, 85.6, 85.5, 85.5, 85.4,
64.5, 60.6, 59.5, 55.3, 38.5, 26.8, 23.6, 14.2, 12.2, 12.1. HRMS
(FAB) calcd for MH+ (C32H34FeNO7) 600.1685, found, 600.1685.
Further purification by flash chromatography (1.5% CH3OH in CH2-
Cl2) afforded the other diastereomer (160 mg, 40%). Rf ) 0.30
(1.5% MeOH in CH2Cl2). [R]D ) -16.1 (c ) 4.12, CHCl3). H
NMR (400 MHz, CDCl3): δ7.21-7.06 (7H), 6.87 (d, J ) 8.8 Hz,
2H), 5.94 (d, J ) 1.2 Hz, 1H), 5.20 (dd, J ) 5.2, 1.2 Hz, 1H),
5.00-4.80 (s, br, 1H), 4.45-4.20 (s, br, 1H), 4.14 (q, J ) 7.2 Hz,
2H), 3.80 (s, 3H), 3.35 (d, J ) 6.0 Hz, 1H), 3.17 (dd, J ) 13.2, 8.0
Hz, 1H), 2.98 (dd, J ) 12.8, 8.8 Hz, 1H), 1.95-1.35 (4H), 1.28 (s,
9H), 1.26 (t, J ) 7.2 Hz, 3H). 13C NMR (50 MHz, CDCl3): δ
173.7, 167.9, 159.1, 137.7, 129.9, 129.6, 129.5, 128.4, 128.3, 126.5,
114.3, 114.2, 84.6, 84.2, 73.5, 63.7, 60.7, 59.5, 55.4, 26.3, 24.7,
14.2, 12.4. HRMS (FAB) calcd for MH+ (C32H34FeNO7) 600.1685,
found, 600.1684.
25
1
[(2R)-Ethyl 2-[(3S,4S,5S)-6,9,η-3-benzyl-2-(4-methoxybenzyl)-
1-oxo-2-azaspiro[4.5]deca-6,8-dien-4-yl]propanoate]tricarbony-
liron (20a) and [(2R)-Ethyl 2-[(3S,4S,5R)- 6,9,η-3-benzyl-2-
(4-methoxybenzyl)-1-oxo-2-azaspiro[4.5]deca-6,8-dien-4-yl]pro-
panoate]tricarbonyliron (20a′). According to the general procedure
for photothermally induced cyclizaton, a mixture of 18a and 18b
(22.5 mg, 37.6 µmol) was refluxed in benzene (5.5 mL) in a dried
quartz tube for 5.5 h to afford inseparable 20a and 20a′ (15.1 mg,
67%) and the diene from demetallation of 20a and 20a′ (0.7 mg,
4%) and the Diels-Alder reaction products 22a and 22b (2.0 mg
12%). 20a and 20a′: Rf ) 0.36 (Hex:EA/2:1). 1H NMR (400 MHz,
CDCl3), mixture of two isomers: δ7.34-6.76 (18H, two isomers),
5.77-5.74 (m, 1H, one isomer), 5.54-5.49 (2H, two isomers),
5.24-5.21 (m, 1H, another isomer), 4.87 (ABq, J ) 14.8 Hz, 1H,
another isomer), 4.67 (ABq, J ) 14.4 Hz, 1H, one isomer), 3.78
(s, 3H, one isomer), 3.77 (s, 3H, another isomer), 4.00-2.3 (20H,
two isomers), 2.20-1.80 (4H, two isomers), 1.13 (t, J ) 6.8 Hz,
3H, another isomer), 0.99 (t, J ) 7.2 Hz, 3H, one isomer), 0.59 (d,
J ) 7.2 Hz, 3H, one isomer), 0.42 (d, J ) 6.8 Hz, 3H, another
isomer). 13C NMR (100 MHz, CDCl3): δ 211.6, 177.6, 176.7,
174.8, 174.7, 159.5, 159.4, 137.8, 137.6, 130.6, 130.5, 130.0, 129.7,
129.0, 128.9, 128.6, 128.3, 127.2, 126.9, 114.2, 114.1, 8.5, 86.9,
86.0, 82.5, 68.2, 63.0, 60.8, 60.7, 59.8, 59.2, 58.4, 57.8, 55.4, 51.1,
50.6, 50.0, 47.6, 45.7, 45.5, 45.1, 41.0, 40.3, 39.4, 38.8, 34.0, 14.2,
13.9, 10.7, 10.5. HRMS (FAB) calcd for MH+ (C32H34FeNO7)
600.1685, found, 600.1670. 22a and 22b: Rf ) 0.40 (Hex:EA/2:
25
2:1). [R]D ) -5 (c ) 1.12, CHCl3). 1H NMR (400 MHz,
CDCl3): δ7.30-7.20 (3H), 7.05 (d, J ) 6.4 Hz, 2H), 6.90 (d, J )
8.4 Hz, 2H), 6.79 (d, J ) 8.8 Hz, 2H), 4.98 (ABq, J ) 14.8 Hz,
1H), 3.99-3.76 (2H), 3.78 (s, 3H), 3.72 (ABq, J ) 14.8 Hz, 1H),
3.22-3.18 (m, 1H), 2.98 (dd, J ) 14.0, 6.4 Hz, 1H), 2.83 (dd, J )
14.0, 7.2 Hz, 1H), 2.41-2.37 (m, 1H), 2.32 (dd, J ) 14.8, 4.4 Hz,
1H), 1.94-1.87 (m, 1H), 1.83 (dd, J ) 14.8, 10.4 Hz, 1H), 1.85-
1.76 (1H), 1.74-1.64 (2H), 1.59-1.24 (6H), 1.09 (t, J ) 6.8 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 178.6, 172.5, 159.2, 138.2,
129.6, 129.5, 128.9, 128.8, 126.9, 114.1, 61.8, 60.7, 55.4, 46.3,
44.3, 41.9, 40.9, 35.6, 35.4, 29.1, 25.6, 22.5, 22.4, 14.3. HRMS
(FAB) calcd for MH+ (C28H36NO4) 450.2644, found, 450.2649.
25
12b: Rf ) 0.60 (Hex:EA/2:1). [R]D ) -72 (c ) 0.85, CHCl3).
1H NMR (400 MHz, C6D6): δ7.03-6.94 (5H), 6.83 (d, J ) 8.8
Hz, 2H), 6.61 (d, J ) 8.8 Hz, 2H), 5.20 (ABq, J ) 14.8 Hz, 1H),
4.0-3.95 (m, 1H), 3.80-3.65 (2H), 3.22 (ABq, J ) 14.8 Hz, 1H),
3.18 (s, 3H), 2.80-2.70 (2H), 2.47 (dd, J ) 14.0, 8.8 Hz, 1H),
2.43-2.37 (m, 1H), 2.22-2.08 (3H), 1.76-1.68 (2H), 1.66-1.58
(m, 1H), 1.50-1.42 (2H), 1.17-1.05 (3H), 0.84 (t, J ) 6.8 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ 178.8, 172.5, 159.0, 139.1,
129.3, 129.2, 129.1, 128.9, 126.8, 114.1, 60.9, 57.9, 55.4, 44.7,
44.4, 44.3, 37.7, 34.4, 31.3, 30.9, 25.9, 22.3, 22.2, 14.3. HRMS
(FAB) calcd for MH+ (C28H36NO4) 450.2644, found, 450.2646.
[(4S,2E)-Ethyl 4-(N-(4-methoxybenzyl)cyclohexa-1,3-diene-
carboxamido)-2-methyl-5-phenylpent-2-enoate]tricarbonylir-
on (18a) and (18b). To a solution of methanesulfonyl chloride (76.6
µL, 0.99 mmol) in freshly distilled CH2Cl2 (2.5 mL) under argon
in a dried round-bottom flask at 0 °C was slowly added a solution
of carboxylic acid 8 (175 mg, 0.66 mmol) and diisopropylethy-
lamine (0.14 mL, 0.86 mmol) in freshly distilled CH2Cl2 (2.0 mL).
Stirring was continued at this temperature for 1 h. Then, diisopro-
pylethylamine (0.24 mL, 1.45 mmol) was added followed by a
solution of amine 16 (465 mg, 1.32 mmol) in freshly distilled CH2-
Cl2 (2.0 mL). The temperature was allowed to rise to rt and the
reaction mixture was stirred for 20 h and was quenched with 1 N
HCl (3 mL), and CH2Cl2 (20 mL) was added. The organic layer
was washed with 1 N HCl (3 mL) and brine (5 mL), was dried
(Na2SO4), was filtered, and was concentrated in vacuo. The crude
products were partially purified by flash chromatography (Hex:
1
1). H NMR (400 MHz, CDCl3) major isomer 22a: δ7.21-6.68
(9H), 6.32 (dd, J ) 6.8, 8.0 Hz, 1H), 6.13 (d, J ) 8.0 Hz, 1H),
5.00 and 3.86 (ABq, J ) 15.2 Hz, 2H), 4.15 (dq, J ) 7.2, 1.2 Hz,
2H), 3.78 (s, 3H), 3.63-3.31 (m, 1H), 3.04-3.00 (m, 1H), 2.89-
2.80 (3H), 1.69-1.50 (3H), 1.24 (t, J ) 6.8 Hz, 3H), 0.85 (s, 3H).
Minor isomer 22b: δ7.21-6.68 (9H), 6.60 (d, J ) 8.0, 1H), 6.22
(dd, J ) 6.0, 8.0 Hz, 1H), 5.07 and 3.86 (ABq, J ) 14.4 Hz, 2H),
4.06 (dq, J ) 7.2, 1.2 Hz, 2H), 3.79 (s, 3H), 2.98-2.92 (m, 1H),
2.72-2.76 (m, 1H), 2.45-2.43 (m, 1H), 1.19 (t, J ) 7.2 Hz, 3H),
0.93 (s, 3H), other peaks overlap with peaks of major isomer. 13
C
NMR (100 MHz, CDCl3): δ 177.1, 177.0, 158.8, 138.5, 134.3,
132.4, 129.2, 129.1, 129.0, 128.6, 126.7, 113.9, 61.3, 59.1, 55.4,
50.6, 49.2, 48.4, 43.6, 41.7, 40.3, 27.6, 20.9, 20.3, 14.4. HRMS
(FAB) calcd for MH+ (C29H34NO4) 460.2488, found, 460.2496.
(2R)-Ethyl 2-[(3S,4S,5S)-3-benzyl-2-(4-methoxybenzyl)-1-oxo-
2-azaspiro[4.5]deca-6,8-dien-4-yl]propanoate and (2R)-Ethyl
2-[(3S,4S,5R)-3-benzyl-2-(4-methoxybenzyl)-1-oxo-2-azaspiro-
[4.5]deca-6,8-dien-4-yl]propanoate. Method A: According to the
general procedure method A for demetallation, E products 20a and
20a′ (13.8 mg, 23.0 µmol) were demetallated at rt for 24 h.
Purification by flash chromatography (Hex:EA/3:1) provided two
isomers (8.5 mg, 81%) as colorless oils. Method B: According to
the general procedure method B for demetallation, E products 20a
and 20a′ (13.0 mg, 21.7 µmol) were demetallated for 24 h at rt.
Purification by preparative TLC (Hex:EA/3:1) afforded two isomers
EA/8:1) to provide 18a and 18b in 81% combined yield. One
25
diastereomer (163 mg, 41%): Rf ) 0.35 (Hex:EA/3:2). [R]D
)
1
+11.9 (c ) 1.20, CHCl3). H NMR (400 MHz, CDCl3): δ7.22-
7.04 (5H), 6.93 (d, J ) 9.6 Hz, 2H), 6.82-6.79 (2H), 6.20 (s, br,
1H), 5.30 (t, J ) 4.8 Hz, 1H), 4.69 (ABq, J ) 16 Hz, 1H), 4.36 (d,
J ) 16.4 Hz, 1H), 4.20-4.04 (3H), 3.80 (s, 3H), 3.45-340 (2H),
2.93 (dd, J ) 13.6, 8.0 Hz, 1H), 1.87-1.68 (3H), 1.41-1.34 (m,
2554 J. Org. Chem., Vol. 72, No. 7, 2007

Dynamic DiastereoselectiVity during Spirocyclization
(8.3 mg, 83%) as colorless oils. One isomer: Rf ) 0.56 (Hex:EA/
The combined organic layer was washed with brine (1 mL), was
dried (Na2SO4), was filtered, and was concentrated in vacuo.
Residual solvent was removed under vacuum oil pump for 12 h to
afford 25 (3.1 mg, 72%, de > 94%) as a colorless oil. Rf ) 0.30
25
1
2:1). [R]D ) +35.0 (c ) 0.26, CHCl3). H NMR (400 MHz,
CDCl3): δ7.33-6.79 (9H), 6.11 (dd, J ) 4.2, 9.6 Hz, 1H), 5.97-
5.92 (m, 1H), 5.77-5.73 (m, 1H), 5.57 (d, J ) 9.6 Hz, 1H), 5.07
(ABq, J ) 14.8 Hz, 1H), 3.90-3.67 (2H), 3.83 (ABq, J ) 14.4
Hz, 1H), 3.80 (s, 3H), 3.57-3.55 (m, 1H), 2.93 (d, J ) 5.6 Hz,
2H, 2.79-2.75 (m, 1H), 2.64 (dd, J ) 3.2, 4.0 Hz, 1H), 2.47-
2.41 (m, 1H), 1.88 (dd, J ) 6.8, 17.2 Hz, 1H), 1.11 (t, J ) 7.2 Hz,
3H), 0.66 (d, J ) 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ
178.6, 175.4, 159.3, 137.7, 130.3, 130.0, 128.9, 128.4, 127.4, 127.1,
125.1, 125.0, 124.3, 114.1, 60.6, 57.9, 55.5, 47.8, 44.6, 44.4, 40.6,
40.1, 34.6, 14.2, 12.8. HRMS (FAB) calcd for MH+ (C29H34NO4)
460.2488, found, 460.2449. The other isomer: Rf ) 0.64 (Hex:
EA/2:1). [R]D25 ) -86.0 (c ) 0.45, CHCl3). 1H NMR (400 MHz,
CDCl3): δ7.31-6.80 (9H), 6.04-5.98 (2H), 5.89-5.85 (m, 1H),
5.69 (d, J ) 8.0 Hz, 1H), 4.89 (ABq, J ) 14.4 Hz, 1H), 3.98 (ABq,
J ) 14.4 Hz, 1H), 3.79 (s, 3H), 3.75-3.67 (m, 1H), 3.49-3.38
(2H), 3.04-2.96 (2H), 2.74 (dd, J ) 13.6, 8.0 Hz, 1H), 2.49-2.48
(m, 1H), 2.45-2.40 (m, 1H), 2.21 (dd, J ) 19.6, 6.4 Hz, 1H), 1.02
(t, J ) 7.6 Hz, 3H), 0.61 (d, J ) 7.2 Hz, 3H). 13C NMR (100
MHz, CDCl3): δ 177.5, 174.7, 159.4, 137.9, 130.7, 130.5, 129.8,
128.8, 128.7, 126.8, 126.0, 124.4, 124.3, 114.2, 60.7, 58.0, 55.5,
48.3, 47.2, 45.1, 43.1, 41.0, 26.2, 14.1, 11.9. HRMS (FAB) calcd
for MH+ (C29H34NO4) 460.2488, found, 460.2496.
1
(Hex:EA/2:1). H NMR (400 MHz, CDCl3): δ7.40-6.82 (14H),
4.96 and 3.93 (ABq, J ) 14.8 Hz, 2H), 3.81 (s, 3H), 3.44 (q, J )
0.8 Hz, 3H), 3.39 (dd, J ) 6.8, 10.8 Hz, 1H), 3.18-3.14 (2H),
3.08 (dd, J ) 8.0, 10.8 Hz, 1H), 2.57 (dd, J ) 10.4, 14.0 Hz, 1H),
2.14 (s, 1H), 2.00-1.69 (6H), 1.60-1.14 (5H), 0.31 (d, J ) 6.8
Hz, 3H). 19F NMR (400 MHz, CDCl3): δ67.49 (s, 3F, major
isomer), 67.53 (s, 3F, minor isomer). 13C NMR (100 MHz,
CDCl3): δ 179.1, 166.3, 159.4, 138.0, 132.3, 130.7, 129.8, 129.5,
129.2, 128.6, 127.5, 127.2, 114.1, 108.2, 77.4, 76.7, 69.4, 57.8,
55.5, 46.7, 44.4, 41.9, 40.4, 37.5, 31.5, 28.5, 25.6, 23.0, 22.3, 11.6.
HRMS (FAB) calcd for MH+ (C37H43F3NO5) 638.3093, found,
638.3060.
[(2S)-Methyl 2-(N-(4-methoxybenzyl)cyclohexa-1,3-dienecar-
boxamido)-3-phenylpropanoate]tricarbonyliron (33). To a solu-
tion of methanesulfonyl chloride (0.17 mL, 2.16 mmol) in freshly
distilled CH2Cl2 (8 mL) at 0 °C under argon in a dried round-
bottom flask was slowly added a solution of carboxylic acid 8 (382
mg, 1.44 mmol) and diisopropylethylamine (0.31 mL, 1.87 mmol)
in freshly distilled CH2Cl2 (5 mL). Stirring was continued at this
temperature for 1 h, and then diisopropylethylamine (0.52 mL, 3.17
mmol) was added followed by a solution of amine 31 (777 mg,
2.60 mmol) in freshly distilled CH2Cl2 (4 mL). The temperature
was raised to 40 °C and the reaction mixture was stirred for 24 h.
After the reaction mixture was cooled to rt, CH2Cl2 (30 mL) was
added and the solution was washed with 1 N HCl (20 mL × 3)
and brine (20 mL × 2), was dried (Na2SO4), was filtered, and was
concentrated in vacuo. The crude products were purified by flash
chromatography (Hex:EA/4:1) to provide 33 as a yellow viscous
liquid. One isomer was obtained in 38% yield after a further
purification by gravity chromatography (1% MeOH in CH2Cl2).
Rf ) 0.55 (Hex:EA/2:1). [R]D25 ) -84 (c ) 1.21, CHCl3). 1H NMR
(400 MHz, CDCl3): δ7.27-6.76 (9H), 6.21 (s, br, 1H), 5.30 (s,
br, 1H), 4.76 (ABq, J ) 14.8 Hz, 1H), 3.84-3.78 (br, 1H), 3.80
(s, 3H), 3.64-3.58 (br, 1H), 3.58 (s, 3H), 3.44-3.22 (3H), 1.95-
1.41 (4H). 13C NMR (100 MHz, CDCl3): δ173.6, 171.2, 159.5,
130.2, 129.9, 128.6, 126.8, 114.1, 113.9, 110.0, 86.3, 85.7, 69.1,
64.7, 60.4, 55.5, 54.5, 52.1, 35.0, 27.2, 23.6. HRMS (FAB) calcd
for MH+ (C28H28FeNO7) 546.1216, found, 546.1208. The other
(2R)-Ethyl 2-[(3S,4S)-3-benzyl-2-(4-methoxybenzyl)-1-oxo-2-
azaspiro[4.5]decadien-4-yl]propanoate (24). Following the pro-
cedure used to prepare 12a and 12b, the (2R)-ethyl 2-[(3S, 4S)-3-
benzyl-2-(4-methoxybenzyl)-1-oxo-2-azaspiro[4.5]deca-6,8-dien-4-
yl]propanoate mixture (8.5 mg, 18.5 µmol) was hydrogenated to
afford 24 (9.3 mg, 88%) as a colorless oil, which was purified by
preparative TLC (2% MeOH in CH2Cl2). Rf ) 0.30 (2% MeOH in
CH2Cl2). [R]D25 ) -14.9 (c ) 0.68, CHCl3). 1H NMR (400 MHz,
CDCl3): δ7.3-6.79 (9H), 4.81 (ABq, J ) 14.8 Hz, 1H), 3.95 (ABq,
J ) 14.4 Hz, 1H), 3.79 (s, 3H), 3.75-3.67 (m, 1H), 3.54-3.50
(m, 1H), 3.42-3.34 (m, 1H), 3.05 (dd, J ) 5.6, 13.2 Hz, 1H), 2.71
(dd, J ) 8.4, 13.6 Hz, 1H), 2.58-2.52 (m, 1H), 2.46-2.45 (m,
1H), 1.90-1.60 (6H), 1.55-1.23 (4H), 1.03 (t, J ) 6.8 Hz, 3H),
0.62 (d, J ) 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ 179.0,
175.1, 159.3, 138.2, 130.5, 129.7, 128.9, 128.8, 126.8, 114.0, 60.6,
58.0, 55.4, 46.5, 44.6, 43.7, 41.1, 38.7, 37.2, 28.7, 25.7, 23.1, 22.6,
14.2, 11.3. HRMS (FAB) calcd for MH+ (C29H38NO4) 464.2800,
found, 464.2820.
25
isomer was obtained in 37% yield. Rf ) 0.45 (Hex:EA/2:1). [R]D
(2R)-2-[(3S,4S)-3-Benzyl-2-(4-methoxybenzyl)-1-oxo-2-azaspiro-
[4.5]decadien-4-yl]propyl (2S)-3,3,3-trifluoro-2-methoxy-2-phe-
nylpropanoate (25). To a solution of 24 (5.3 mg, 11.4 µmol) in
freshly distilled ether (0.2 mL), was carefully added LiBH4 (1.51
mg, 68.6 µmol) at rt. After stirring was continued for 2 h, the
reaction mixture was quenched with water (1 mL) and was extracted
with ether (3 mL × 3). The ether layer was washed with brine (1
mL), was dried (Na2SO4), was filtered, and was concentrated in
vacuo. The crude product was purified by preparative TLC (2%
MeOH in CH2Cl2) to afford (2R)-2-[(3S, 4S)-3-benzyl-2-(4-meth-
oxybenzyl)-1-oxo-2-azaspiro[4.5]decadien-4-yl]propanol (4.3 mg,
) -135 (c ) 0.68, CHCl3). 1H NMR (400 MHz, CDCl3): δ7.28-
7.09 (7H), 6.88 (d, J ) 8.8 Hz, 2H), 6.03 (d, J ) 4.4 Hz, 1H),
5.23 (dd, J ) 6.0, 4.4 Hz, 1H), 4.92 (ABq, J ) 16.0 Hz, 1H),
3.88-3.73 (2H), 3.81 (s, 3H), 3.67 (s, 3H), 3.55 (dd, J ) 14.4, 6.0
Hz, 1H), 3.77 (d, 5.6 Hz, 1H), 3.09 (dd, J ) 14.0, 7.6 Hz, 1H),
1.96-1.44 (4H). 13C NMR (100 MHz, CDCl3): δ195.8, 173.5,
170.8, 159.5, 139.1, 129.6, 129.0, 128.7, 127.7, 126.7, 114.4, 85.2,
84.6, 64.0, 61.3, 55.5, 53.1, 52.4, 35.6, 26.3, 24.7. HRMS (FAB)
calcd for MH+ (C28H28FeNO7) 546.1216, found, 546.1202.
[N-(4-Methoxybenzyl)-N-((2S)-1-formyl-2-phenylethyl)cyclo-
hexa-1,3-diene carboxamide]tricarbonyliron (34). To a solution
of ester 33 (503 mg, 0.92 mmol) in Et2O (4.4 mL) at -78 °C was
added dropwise DIBAl-H (1.5 M in toluene, 2.45 mL, 3.68 mmol).
After stirring at this temperature for 15 min, MeOH (4.4 mL) was
added slowly, followed by saturated NaK tartrate (8 mL) at -78
°C. Then, the reaction mixture was allowed to warm to rt and was
extracted with diethyl ether (15 mL × 3). The combined extract
was dried (Na2SO4) and concentrated. Flash chromatography (Hex:
EA/3:1) provided pure products 34. One diastereomer (208 mg,
44%): Rf ) 0.60 (Hex:EA/2:1). [R]D25 ) -79 (c ) 1.71, CHCl3).
1H NMR (400 MHz, CDCl3): δ9.35 (s, 1H), 7.36-6.85 (9H), 6.25
(d, J ) 4.0 Hz, 1H), 5.35 (dd, J ) 6.0, 4.8 Hz, 1H), 4.96 (ABq, J
) 14.0 Hz, 1H), 3.80 (s, 3H), 3.53-3.51 (m, 1H), 3.37-3.30 (2H),
3.16-3.05 (2H), 2.02-1.41 (4H). 13C NMR (100 MHz, CDCl3):
δ197.2, 173.7, 159.8, 138.8, 129.9, 129.7, 128.8, 127.4, 127.0,
114.9, 86.3, 85.9, 67.3, 65.8, 65.6, 55.5, 53.8, 32.7, 27.7, 23.1.
25
90%) as a colorless oil. Rf ) 0.25 (2% MeOH in CH2Cl2). [R]D
) -3.4 (c ) 0.36, CHCl3). 1H NMR (400 MHz, CDCl3): δ7.38-
6.86 (9H), 4.95 and 4.07 (ABq, J ) 14.4 Hz, 2H), 3.81 (s, 3H),
3.26 (dd, J ) 4.0, 12.8 Hz, 1H), 3.12 (dd, J ) 4.4, 7.6 Hz, 1H),
2.79 (dd, J ) 4.2, 11.2 Hz, 1H), 2.54 (dd, J ) 11.6, 12.8 Hz, 1H),
2.33-2.28 (2H), 1.85-1.26 (12H), 0.24 (d, J ) 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 179.7, 159.4, 138.4, 130.7, 129.8,
129.1, 128.8, 127.4, 114.2, 65.6, 57.1, 55.5, 46.6, 44.4, 39.8, 39.1,
37.8, 34.0, 28.5, 25.7, 23.2, 22.6, 11.2. HRMS (FAB) calcd for
MH+ (C27H36NO3) 422.2695, found, 422.2698.
To a solution of this alcohol (2.9 mg, 6.9 µmol) in freshly
distilled toluene (0.15 mL) was added diisopropylethylamine (11.5
µL, 69 µmol) and Mosher’s chloride (10.4 µL, 55.0 µmol). Then,
the reaction mixture was heated to 100 °C and was stirred for 16
h at this temperature. The cooled reaction mixture was quenched
with 1 N HCl (0.5 mL) and was extracted with ether (1 mL × 3).
J. Org. Chem, Vol. 72, No. 7, 2007 2555

Pearson et al.
HRMS (FAB) calcd for MH+ (C27H26FeNO6) 516.1112, found,
and 20a′ from E-substrates were also obtained in 3% yield and
Diels-Alder products 39 in 14% yield. Characterizations for 39
are included in the Supporting Information.
516.1100. The other diastereomer (171 mg, 36%): Rf ) 0.50 (Hex:
25
1
EA/2:1). [R]D ) -115 (c ) 1.36, CHCl3). H NMR (400 MHz,
CDCl3): δ9.50 (s, 1H), 7.31-6.88 (9H), 6.06 (d, J ) 4.0 Hz, 1H),
5.27 (dd, J ) 5.6, 5.2 Hz, 1H), 5.00 and 3.77 (ABq, J ) 16.8 Hz,
2H), 3.80 (s, 3H), 3.56 (dd, J ) 14.0, 5.2 Hz, 1H), 3.47-3.40 (2H),
3.02 (dd, J ) 14.0, 8.0 Hz, 1H), 1.98-1.47 (4H). 13C NMR (100
MHz, CDCl3): δ196.4, 173.8, 159.7, 138.8, 129.4, 129.0, 128.4,
127.4, 126.9, 114.9, 85.3, 85.2, 69.5, 66.6, 64.6, 55.6, 52.4, 33.5,
26.7, 24.5. HRMS (FAB) calcd for MH+ (C27H26FeNO6) 516.1112,
found, 516.1098.
(2S)-Ethyl 2-[(3S,4S,5S)-3-benzyl-2-(4-methoxybenzyl)-1-oxo-
2-azaspiro[4.5]deca-6, 8-dien-4-yl]propanoate (29a) and (2S)-
Ethyl 2-[(3S,4S,5R)-3-benzyl-2-(4-methoxybenzyl)-1-oxo-2-aza-
spiro[4.5]deca-6,8-dien-4-yl]propanoate (29b). According to the
general procedure for demetallation method B, Z-products 28a and
28b (15.6 mg, 26.0 µmol) and sat. CuCl2 solution in EtOH (0.7
mL) were mixed. Stirring was continued at rt for 24 h. The crude
products were purified by preparative TLC (Hex:EA/3:1) to afford
29a and 29b in 80% combined yield. 29a (3.7 mg, 31%, colorless
[(4S,2Z)-Ethyl 4-(N-(4-methoxybenzyl)cyclohexa-1,3-diene-
carboxamido)-2-methyl-5-phenylpent-2-enoate]tricarbonylir-
on (35a) and (35b). To a solution of ethyl 2-[bis(2,2,2-trifluoro-
ethyl)phosphono]propanoate (347 mg, 1.00 mmol) in THF (6 mL)
at 0 °C was carefully added potassium hydride (35% in oil, 68.7
mg, 0.60 mmol). The reaction was maintained at 0 °C for 30 min
and then was cooled to -78 °C, and aldehyde 34 (344 mg, 0.67
mmol) in THF (5 mL) was added. The reaction mixture was stirred
at -78 °C for 3 h and then was allowed to warm to 0 °C, was
quenched with 1 N HCl (25 mL), and was extracted with diethyl
ether (20 mL × 3). The combined organic layer was washed with
brine (10 mL × 2) and was dried (Na2SO4). The solvent was
evaporated in vacuo and the residue was further purified by flash
chromatography (Hex:EA/6:1) to provide inseparable products 35a
25
oil): Rf ) 0.40 (Hex:EA/2:1). [R]D ) +37 (c ) 0.31, CHCl3).
1H NMR (400 MHz, CDCl3): δ 7.31-6.82 (9H), 6.06 (dd, J )
10.0, 5.2 Hz, 1H), 5.94-5.90 (m, 1H), 5.75-5.71 (m, 1H), 5.55
(d, J ) 9.6 Hz, 1H), 4.87 and 4.24 (ABq, J ) 15.2 Hz, 2H), 3.99-
3.89 (2H), 3.80 (s, 3H), 3.67-3.63 (m, 1H), 2.87-2.74 (3H), 2.45-
2.38 (m, 1H), 2.22 (dd, J ) 4.4, 4.8 Hz, 1H), 1.85 (dd, J ) 17.6,
5.6 Hz, 1H), 1.16 (t, J ) 7.2 Hz, 3H), 0.74 (d, J ) 7.2 Hz, 3H).
13C NMR (100 MHz, CDCl3): δ178.7, 175.0, 159.3, 137.3, 130.2,
130.0, 128.8, 127.1, 126.7, 125.7, 124.8, 124.1, 114.1, 60.5, 59.8,
55.5, 47.9, 46.9, 45.3, 40.5, 40.3, 35.2, 16.2, 14.3. HRMS (FAB)
calcd for MH+ (C29H34NO4) 460.2488, found, 460.2475. 29b (5.8
25
mg, 49%, colorless oil): Rf ) 0.60 (Hex:EA/ 2:1). [R]D ) -20
(c ) 0.48, CHCl3). 1H NMR (400 MHz, CDCl3): δ7.28-6.83 (9H),
6.03-5.95 (2H), 5.89-5.84 (m, 1H), 5.68 (dd, J ) 8.4, 1.2 Hz,
1H), 4.56 and 4.43 (ABq, J ) 14.8 Hz, 2H), 4.01-3.86 (2H), 3.79
(s, 3H), 3.55-3.51 (m, 1H), 2.93-2.83 (2H), 2.58-2.40 (3H), 2.13
(dd, J ) 3.6, 2.4 Hz, 1H), 1.16 (t, J ) 7.2 Hz, 3H), 0.56 (d, J )
6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ177.6, 174.6, 159.2,
137.8, 131.2, 130.1, 129.8, 129.6, 128.8, 126.9, 126.3, 124.2, 124.0,
114.2, 60.8, 60.7, 55.5, 51.3, 47.5, 46.1, 42.0, 41.0, 26.5, 16.1, 14.2.
HRMS (FAB) calcd for MH+ (C29H34NO4) 460.2488, found,
460.2489.
1
and 35b (251 mg, 70%). Rf ) 0.70 (Hex:EA/2:1). H NMR (400
MHz, CDCl3) two diastereomers: δ7.20-6.56 (10H), 6.22, 5.70
(br, 1H), 5.31, 5.05 (br, 1H), 6.27-4.30 (3H), 3.93 (q, J ) 7.2 Hz,
2H), 3.79, 3.78 (s, 3H), 3.60-3.22 (2H), 2.98 (dd, J ) 12.8, 5.6
Hz, 1H), 1.84, 1.80 (d, J ) 1.2 Hz, 3H), 2.0-1.0 (7H). 13C NMR
(100 MHz, CDCl3): δ 174.3, 173.8, 167.3, 167.2, 159.0, 139.5,
139.2, 129.9, 129.8, 128.9, 128.7, 128.5, 128.4, 126.4, 114.5, 114.3,
114.0, 85.9, 83.8, 71.2, 64.9, 60.8, 60.6, 60.4, 55.5, 55.4, 54.3, 37.8,
27.0, 26.2, 25.5, 23.4, 20.7, 20.5, 14.2. HRMS (FAB) calcd for
MH+ (C32H34FeNO7) 600.1685, found, 600.1682.
[(3S,4S,5S)-6,9,η-3-Benzyl-4-((1S)-formyl-1-ethyl)-2-(4-meth-
oxybenzyl)-1-oxo-2-azaspiro[4.5] deca-6,8-diene]tricarbonyliron
(40a) and [(3S,4S,5R)-6,9,η-3-Benzyl-4-((1S)-formyl-1-ethyl)-2-
(4-methoxybenzyl)-1-oxo-2-azaspiro[4.5] deca-6,8-diene]tricar-
bonyliron (40b). To a solution of 28a and 28b (21.7 mg, 36.2 µL)
in Et2O (0.3 mL) at -78 °C was added dropwise DIBAl-H solution
(1.5 M in toluene, 0.12 mL 181.1 µL). Stirring was continued for
1 h, and the reaction was quenched slowly with MeOH (0.6 mL)
immediately followed by addition of sat. KNa tartrate solution (1
mL). The product was extracted with Et2O (1.5 mL × 3), and the
organic layer was dried (Na2SO4) and was concentrated, and the
residue was purified by flash chromatography (Hex:EA/3:1) to
afford two diastereomers 40a and 40b (15.6 mg, 77% combined
yield). One isomer (11.1 mg, 55%, pale yellow oil): Rf ) 0.50
[(2S)-Ethyl 2-[(3S,4S,5S)-6,9,η-3-benzyl-2-(4-methoxybenzyl)-
1-oxo-2-azaspiro[4.5]deca-6,8-dien-4-yl]propanoate]tricarbony-
liron (28a) and [(2S)-Ethyl 2-[(3S,4S,5R)- 6,9,η-3-benzyl-2-
(4-methoxybenzyl)-1-oxo-2-azaspiro[4.5]deca-6,8-dien-4-yl]pro-
panoate]tricarbonyliron (28b). According to the general procedure
for photothermally induced cyclization, a mixture of 35a and 35b
(24.3 mg, 0.04 mmol) was refluxed in 5.5 mL of benzene under
CO atmosphere for 5.5 h. Preparative TLC (1% THF in CH2Cl2)
provided two isomers 28a and 28b in 72% combined yield. One
isomer (12.6 mg, 52%, yellow sticky oil): Rf ) 0.55 (Hex:EA/
2:1 two developments). [R]D25 ) +64 (c ) 0.84, CHCl3). 1H NMR
(400 MHz, CDCl3): δ7.35-6.84 (9H), 5.53 (dd, J ) 4.2, 4.2 Hz,
1H), 5.28-5.25 (m, 1H), 4.48 and 4.43 (ABq, J ) 14.8 Hz, 2H),
3.87-3.54 (2H), 3.79 (s, 3H), 3.54-3.50 (m, 1H), 3.36-3.32 (m,
1H), 2.95 (dd, J ) 13.2, 4.4 Hz, 1H), 2.74-2.65 (2H), 2.50 (dd, J
) 6.8, 1.2 Hz, 1H), 2.07 (dd, J ) 2.0, 2.4 Hz, 1H), 2.02-1.92
(2H), 1.05 (t, J ) 7.2 Hz, 3H), 0.56 (d, J ) 7.2 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ211.9, 177.9, 173.8, 159.3, 137.1, 130.5,
130.2, 129.3, 128.9, 127.3, 114.1, 88.5, 82.7, 69.1, 64.0, 60.6, 60.5,
55.5, 51.0, 49.6, 46.3, 41.4, 38.3, 34.3, 15.4, 14.2. HRMS (FAB)
calcd for MH+ (C32H34FeNO7) 600.1685, found, 600.1673. The
other isomer (4.9 mg, 20%, yellow sticky oil): Rf ) 0.65 (Hex:
25
1
(Hex:EA/1:1). [R]D ) +54 (c ) 0.98, CHCl3). H NMR (400
MHz, CDCl3): δ9.12 (s, 1H), 7.35-6.84 (9H), 5.55 (dd, J ) 5.2,
5.2 Hz, 1H), 5.30-5.27 (m, 1H), 4.89 and 4.06 (ABq, J ) 14.8
Hz, 2H), 3.80 (s, 3H), 3.36-3.33 (m, 1H), 3.16-3.12 (m, 1H),
3.06 (dd, J ) 13.2, 4.4 Hz, 1H), 2.72 (dd, J ) 13.6, 9.2 Hz, 1H),
2.67-2.60 (m, 1H), 2.49 (dd, J ) 6.4, 1.2 Hz, 1H), 2.16 (dd, J )
2.0, 2.8 Hz, 1H), 2.01-1.88 (2H), 0.49 (d, J ) 7.2 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ211.8, 202.6, 177.4, 159.5, 136.8,
130.5, 130.1, 129.1, 127.9, 127.5, 114.2, 88.6, 82.7, 68.7, 63.6,
59.4, 55.5, 50.7, 48.4, 46.4, 45.4, 40.7, 34.3, 11.8. HRMS (FAB)
calcd for MH+ (C30H30FeNO6) 556.1423, found, 556.1413. Further
purification by a preparative TLC (1.5% THF in CH2Cl2) provided
the other isomer (4.5 mg, 22%, pale yellow oil). Rf ) 0.60 (Hex:
25
1
EA/2:1 two developments). [R]D ) -10 (c ) 0.38, CHCl3). H
NMR (400 MHz, CDCl3): δ7.30-6.82 (9H), 5.76-7.72 (m, 1H),
5.53-5.50 (m, 1H), 4.66 and 4.11 (ABq, J ) 14.8 Hz, 2H), 3.93-
3.84 (2H), 3.78 (s, 3H), 3.62 (dd, J ) 10.8, 4.0 Hz, 1H), 3.14-
3.10 (2H), 2.91 (dq, J ) 6.8, 2.0 Hz, 1H), 2.80 (dd, J ) 13.2, 4.4
Hz, 1H), 2.2-2.11 (2H), 2.00 (dd, J ) 15.2, 3.6 Hz, 1H), 1.93 (d,
J ) 1.6 Hz, 1H), 1.15 (t, J ) 6.8 Hz, 3H), 0.46 (d, J ) 8.8 Hz,
3H). 13C NMR (100 MHz, CDCl3): δ174.3, 173.8, 167.3, 167.2,
159.0, 139.5, 139.2, 129.9, 129.8, 128.9, 128.7, 128.5, 128.4, 126.4,
114.3, 114.0, 85.9, 83.8, 71.2, 64.9, 60.8, 60.6, 60.4, 55.5, 55.4,
64.3, 37.8, 27.0, 25.5, 23.4, 20.7, 20.5, 14.2. HRMS (FAB) calcd
for MH+ (C32H34FeNO7) 600.1685, found, 600.1673. Products 20a
25
EA/1:1) or 0.70 (1.5% THF in CH2Cl2, three developments). [R]D
1
) -48 (c ) 0.39, CHCl3). H NMR (400 MHz, CDCl3): δ9.20
(d, J ) 1.6 Hz, 1H), 7.33-6.86 (9H), 5.78-5.75 (m, 1H), 5.53
(dd, J ) 6.4, 4.4 Hz, 1H), 4.67 and 4.15 (ABq, J ) 14.4 Hz, 2H),
3.81 (s, 3H), 3.20 (dd, J ) 9.6, 4.0 Hz, 1H), 3.16-3.13 (m, 1H),
3.04 (dd, J ) 13.2, 4.0 Hz, 1H), 2.84-2.80 (m, 1H), 2.76 (d, J )
6.0 Hz, 1H), 2.27 (dd, J ) 13.2, 10.8 Hz, 1H), 2.15 (dd, J ) 15.2,
2.0 Hz, 1H), 2.06-1.99 (2H), 0.39 (d, J ) 7.2 Hz, 3H). 13C NMR
2556 J. Org. Chem., Vol. 72, No. 7, 2007

Dynamic DiastereoselectiVity during Spirocyclization
(100 MHz, CDCl3): δ203.4, 176.3, 159.6, 137.1, 130.5, 129.6,
129.1, 128.1, 127.3, 114.3, 87.1, 85.9, 60.8, 59.9, 59.8, 55.5, 53.3,
52.0, 45.7, 45.5, 40.1, 12.4. HRMS (FAB) calcd for MH+ (C30H30-
FeNO6) 556.1423, found, 556.1392.
(m, 1H), 0.88 (d, J ) 7.2 Hz, 3H), 0.47 (d, J ) 6.4 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ212.3, 176.5, 159.3, 136.6, 130.4,
129.6, 128.8, 128.6, 127.1, 114.3, 86.6, 83.6, 67.8, 65.8, 61.4, 55.5,
54.9, 52.1, 51.4, 44.8, 43.3, 41.3, 40.1, 13.8. HRMS (FAB) calcd
for MH+ (C31H32FeNO5) 554.1630, found, 554.1654.
[(3S,4S,5S)-6,9,η-3-Benzyl-4-((3R)-but-1-en-3-yl)-2-(4-meth-
oxybenzyl)-1-oxo-2-azaspiro[4.5]deca-6,8-diene]tricarbonyliron
(41a) and [(3S,4S,5R)-6,9,η-3-Benzyl-4-((3R)-but-1-en-3-yl)-2-
(4-methoxybenzyl)-1-oxo-2-azaspiro[4.5]deca-6,8-diene]tricarb-
onyliron (41b). To a suspension of methyltriphenylphosphonium
bromide (98 mg, 0.275 mmol) in THF (2.5 mL) at 0 °C was slowly
added n-BuLi (2.5 M solution in hexanes, 0.11 mL, 0.275 mmol).
After 1 h at this temperature, a solution of aldehydes 40a and 40b
(61 mg, 0.11 mmol) in THF (2.5 mL) was added quickly. Stirring
was continued at 0 °C for 10 min and then the reaction was allowed
to reach rt and was maintained at this temperature for 1.5 h. Finally,
the reaction was quenched with 1 N HCl (2 mL) and was extracted
with Et2O (4 mL × 3). The organic layer was dried (Na2SO4) and
was concentrated in vacuo, and the residue was purified by flash
chromatography (Hex:EA/4:1) to afford 41a and 41b (55 mg, 92%
combined yield). One isomer (43 mg, 72%, pale yellow oil): Rf )
0.65 (Hex:EA/2:1). [R]D ) +42 (c ) 0.23, CHCl3). H NMR
(400 MHz, CDCl3): δ 7.36-6.80 (9H), 5.54 (dd, J ) 6.4, 4.4 Hz,
1H), 5.29-5.26 (m, 1H), 4.97-4.88 (m, 1H), 4.85 and 3.94 (ABq,
J ) 14.4 Hz, 2H), 4.69-4.56 (2H), 3.80 (s, 3H), 3.36-3.25 (m,
1H), 3.19-3.16 (m, 1H), 3.09 (dd, J ) 13.2, 4.8 Hz, 1H), 2.75
(dd, J ) 13.6, 9.2 Hz, 1H), 2.63 (dd, J ) 6.4, 1.2 Hz, 1H), 2.50-
2.43 (m, 1H), 2.09 (dd, J ) 16.0, 3.6 Hz, 1H), 2.05-1.93 (2H),
0.35 (d, J ) 6.8 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ211.9,
177.9, 159.4, 137.7, 137.6, 130.7, 130.0, 129.0, 128.5, 127.2, 116.3,
114.0, 88.6, 82.6, 69.0, 63.9, 58.1, 55.5, 50.7, 50.6, 45.1, 41.0, 35.9,
33.4, 16.9. HRMS (FAB) calcd for MH+ (C31H32FeNO5) 554.1630,
found, 554.1627. The other isomer (12 mg, 20%, pale yellow oil):
Rf ) 0.63 (Hex:EA/2:1). [R]D25 ) -63 (c ) 0.19, CHCl3). 1H NMR
(400 MHz, CDCl3): δ7.31-6.84 (9H), 5.74-5.70 (m, 1H), 5.50
(dd, J ) 6.4, 4.4 Hz, 1H), 5.15-5.07 (m, 1H), 4.78-4.65 (m, 2H),
4.70 and 4.03 (ABq, J ) 14.4 Hz, 2H), 3.81 (s, 3H), 3.18-3.10
(2H), 3.03 (dd, J ) 13.2, 4.4 Hz, 1H), 2.89 (d, J ) 6.0 Hz, 1H),
2.69-2.65 (m, 1H), 2.32 (d, J ) 13.2, 10.4 Hz, 1H), 2.12-1.99
(2H), 1.86 (d, J ) 1.2 Hz, 1H), 0.28 (d, J ) 6.8 Hz, 3H). 13C
NMR (100 MHz, CDCl3): δ 177.0, 159.5, 138.5, 137.7, 130.7,
129.7, 128.9, 128.6, 127.1, 116.3, 114.1, 87.0, 85.8, 60.9, 60.0,
58.8, 55.5, 54.0, 52.1, 45.5, 45.3, 40.2, 36.0, 18.0. HRMS (FAB)
calcd for MH+ (C31H32FeNO5) 554.1630, found, 554.1620.
(3S,3aR,4R,5R,5aS)-2-(4-Methoxybenzyl)-3-benzyl-2,3,3a,4,5,-
5a-hexahydro-4,5-dimethylindeno[1-c]pyrrol-1-one (43). Ac-
cording to the general procedure method B for demetallation,
compound 42 (10.0 mg, 18.0 µmol) was treated with sat. CuCl2
solution in EtOH (0.5 mL) at rt for 24 h. The purification by
preparative TLC (Hex:EA/3:1) afforded 43 (5.3 mg, 72%) as a
25
colorless oil. Rf ) 0.40 (Hex:EA/2:1). [R]D ) -20 (c ) 0.45,
CHCl3). 1H NMR (400 MHz, CDCl3/C6D6)1/3): δ7.11-6.73 (9H),
5.84-5.70 (2H), 5.55-5.45 (2H), 5.22 and 3.70 (ABq, J ) 14.4
Hz, 2H), 3.44-3.40 (m, 1H), 3.34-3.32 (m, 1H), 3.35 (s, 3H),
2.87 (dd, J ) 13.2, 4.0 Hz, 1H), 2.32 (dd, J ) 13.6, 9.2 Hz, 1H),
2.26 (dd, J ) 9.2, 1.6 Hz, 1H), 1.45-1.40 (m, 1H), 1.35-1.28 (m,
1H), 0.77 (d, J ) 6.4 Hz, 3H), 0.22 (d, J ) 6.8 Hz, 3H). 13C NMR
(100 MHz, CDCl3): δ178.4, 159.4, 137.4, 130.2, 129.8, 128.8,
127.2, 126.9, 125.3, 123.3, 123.30, 114.3, 100.4, 56.7, 56.2, 55.5,
55.3, 47.0, 44.7, 44.4, 44.3, 40.9, 14.2, 13.2. HRMS (FAB) calcd
for MH+ (C28H32NO2) 414.2433, found, 414.2426.
25
1
[N-(4-Methoxybenzyl)-N-((2S,3Z)-4-methyl-1-phenylhexa-3,5-
dien-2-yl)cyclohexa-1, 3-dienecarboxamide]tricarbonyliron (48).
Following the procedure for preparation of 18a and 18b, to a
solution of methanesulfonyl chloride (7.4 µL, 0.096 mmol) in
freshly distilled CH2Cl2 (0.3 mL) was slowly added a solution of
carboxylic acid 8 (17 mg, 0.065 mmol) and diisopropylethylamine
(13.8 µL, 0.083 mmol) in freshly distilled CH2Cl2 (0.3 mL). Stirring
was continued for 1 h, and then diisopropylethylamine (23.3 µL,
0.141 mmol) was added followed by the solution of amine 47 (32
mg, 0.104 mmol) in freshly distilled CH2Cl2 (0.3 mL). The reaction
was maintained at rt for 24 h, and then the temperature was allowed
to rise to 40 °C, and the reaction mixture was stirred for 10 h. The
crude products were purified by flash chromatography (Hex:EA/
4:1) to provide two inseparable diastereomers 48 (29 mg, 83%). Rf
1
) 0.75 (Hex:EA/2:1). H NMR (400 MHz, CDCl3) two diastere-
omers: δ7.20-6.77 (9H), 6.26-5.60 (3H), 5.40-4.20 (6H), 3.81
(s, 3H), 3.50-3.14 (2H), 2.88-2.81 (m, 1H), 2.10-1.40 (4H), 1.73,
1.72 (d, J ) 1.2 Hz, 3H). 13C NMR (100 MHz, CDCl3): δ174.4,
173.7, 168.5, 168.2, 159.0, 139.4, 135.5, 133.3, 133.0, 129.8, 129.7,
128.9, 128.6, 128.5, 128.4, 128.3, 128.1, 126.4, 115.3, 114.3, 114.2,
88.9, 88.8, 86.3, 86.2, 85.7, 84.9, 84.2, 74.2, 71.6, 64.6, 64.0, 63.8,
63.5, 58.1, 55.5, 55.4, 52.5, 40.7, 39.8, 26.8, 26.5, 25.7, 25.6, 24.9,
24.0, 22.8, 19.9, 19.8. HRMS (FAB) calcd for MH+ (C31H32FeNO5)
554.1630, found, 554.1613.
[(3S,3aR,4R,5R,5aS)-6,9, η-3-Benzyl-2-(4-methoxybenzyl)-2,3,-
3a,4,5,5a-hexahydro-4,5-dimethylindeno[1-c]pyrrol-1-one]tricar-
bonyliron (42). According to the general photothermally induced
cyclization procedure, a mixture of 41a and 41b (8.3 mg, 15 µmol)
was heated at 160 °C in mesitylene (2.3 mL) under CO atmosphere
for 9 h. Preparative TLC (Hex:EA/3:1) provided compound 42 (4.3
mg, 52%). Starting material (25%) was also recovered. Rf ) 0.60
Acknowledgment. We thank the National Science Founda-
tion for financial support (grant CHE-0449642).
Supporting Information Available: Experimental procedures
for preparation of compounds 6-7, 13-17, 23, 31-32, 36-39,
and 44-47 and copies of NMR spectra of all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
25
1
(Hex:EA/ 2:1). [R]D ) +23 (c ) 0.80, CHCl3). H NMR (400
MHz, CDCl3): δ7.33-6.83 (9H), 5.37 (dd, J ) 6.4, 4.4 Hz, 1H),
5.31-5.28 (m, 1H), 5.12 and 3.89 (ABq, J ) 14.8 Hz, 2H), 3.81
(s, 3H), 3.42-3.87 (m, 1H), 2.94 (d, J ) 6.4 Hz, 1H), 2.83-2.74
(2H), 2.39 (dd, J ) 9.2, 3.6 Hz, 1H), 2.35-2.28 (m, 1H), 2.17
(dd, J ) 6.4, 1.2 Hz, 1H), 2.11 (d, J ) 8.4 Hz, 1H), 1.24-1.19
JO0625608
J. Org. Chem, Vol. 72, No. 7, 2007 2557